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Phase II Trial of Intravesical Gemcitabine in Bacille Calmette-Guérin–Refractory Transitional Cell Carcinoma of the Bladder

Guido Dalbagni, Paul Russo, Bernard Bochner, Leah Ben-Porat, Joel Sheinfeld, Pramod Sogani, Machelle S. Donat, Harry W. Herr, Dean Bajorin

From the Department of Urology, Division of Epidemiology and Biostatistics, the Genitourinary Oncology Service, Division of Solid Tumor Oncology, and the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

Address reprint requests to Guido Dalbagni, MD, Department of Urology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, C-1168, New York, NY 10021; e-mail: dalbagng{at}mskcc.org

	ABSTRACT

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PURPOSE: The aim of this phase II study was to determine the efficacy of gemcitabine administered as an intravesical agent in patients with bacille Calmette-Guérin (BCG) –refractory transitional cell carcinoma of the bladder.

PATIENTS AND METHODS: Patients with superficial bladder cancer refractory or intolerant to intravesical BCG therapy and refusing a cystectomy were considered eligible for the trial. Eligible patients received two courses of intravesical gemcitabine twice weekly at a dose of 2,000 mg/100 mL for 3 consecutive weeks, with each course separated by 1 week of rest. Patients were evaluated for response at 8 weeks, then every 3 months to 1 year.

RESULTS: Thirty eligible patients were included on study. The median follow-up for all the patients was 19 months (range, 0 to 35 months). Of the 30 patients, 15 (50%; 95% CI, 32% to 68%) achieved a complete response (CR). Twelve patients had tumor recurrence with a median recurrence-free survival time of 3.6 months (95% CI, 2.9 to 11.0 months). Two patients maintained a CR at 23 and 29 months, respectively. The 1-year recurrence-free survival rate for patients with a CR was 21% (95% CI, 0% to 43%). Two patients progressed to a higher stage while receiving gemcitabine treatment. The median follow-up for patients who did not have a progression or a cystectomy was 19 months (range, 2 to 35 months). Eleven patients (37%) underwent a cystectomy subsequent to gemcitabine therapy.

CONCLUSION: Gemcitabine has activity in a high-risk patient population and remains a viable option for some patients who refuse cystectomy.

	INTRODUCTION

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Bladder cancer is the fifth most common cancer in the United States.¹ Seventy percent of bladder tumors are superficial at presentation and include carcinoma in situ (cis), Ta, and T1 disease. Despite conservative management by endoscopic resection, 60% to 70% of superficial tumors recur,² and 20% to 30% of recurrent tumors will progress to a higher stage or grade.³ Bacille Calmette-Guerin (BCG) is the most effective agent in the treatment of cis⁴ and decreases the rate of progression^5-10; however, only two thirds of patients respond to BCG, and one third of the responders will develop recurrent disease, which is associated with a poor prognosis.^11,12 Given that the only other accepted standard treatment for BCG-refractory urothelial cancer is radical cystectomy, identification of active agents in this disease is clearly warranted.

Gemcitabine (2',2'-difluoro-2'-deoxycytidine; Gemzar, Eli Lilly and Co, Indianapolis, IN) is a novel deoxycytidine analog with a broad spectrum of antitumor activity. This agent is highly effective (overall response rates ranging from 22.5% to 28%) and well tolerated as both first- and second-line single-agent therapy for the treatment of metastatic transitional cell carcinoma (TCC).^13-15 Studies have reported a low incidence of systemic side effects. A randomized, multicenter, phase III study demonstrated that patients with unresectable or metastatic disease treated with gemcitabine plus cisplatin had a similar survival to patients treated with MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin), and gemcitabine plus cisplatin had a better safety profile and tolerability.^16,17

We reported a phase I study of intravesical gemcitabine twice a week for three weeks, followed by a second cycle after a week of rest, in a heavily pretreated population with BCG-refractory TCC. This study demonstrated that intravesical gemcitabine was well tolerated, with minimal bladder irritation and acceptable myelosuppression. Serum levels of gemcitabine were undetectable at concentrations of 5 mg/mL, 10 mg/mL, and 15 mg/mL. However, serum gemcitabine was detected at a concentration of 20 mg/mL. Complete response (CR), defined as a negative post-treatment cystoscopy including a biopsy of the urothelium and a negative cytology, was achieved in seven (39%) of 18 patients.¹⁸ This first reported phase I study demonstrated excellent tolerability to intravesical gemcitabine given twice a week, with doses up to 2,000 mg per instillation (20 mg/mL). Based on the results of this phase I study, we recommended a phase II dose of 2,000 mg twice a week (15 mg/mL) for 3 weeks, followed by a second course after a week of rest.

Thus, the objectives of the study were to determine the efficacy of intravesical gemcitabine in patients with BCG-refractory or BCG-intolerant disease, for whom a cystectomy was recommended as standard management, but refused.

	PATIENTS AND METHODS

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Inclusion Criteria
All patients in this trial had superficial TCC refractory or intolerant to BCG therapy, for which a cystectomy was recommended but refused. Clinical stages of disease included refractory cis, multiple unresected T1, and uncontrollable Ta. Additional eligibility criteria included pathologic confirmation by the Department of Pathology at Memorial Sloan-Kettering Cancer Center (MSKCC), a Karnofsky performance status 70%, adequate marrow function defined as granulocytes greater than 1,500 cells/mm³ and platelets more than 150,000 cells/mm³, age 18 years, adequate hepatic function defined as total bilirubin less than 1.5x normal, AST less than 2x normal, and informed consent. Exclusion criteria included prior radiation to the pelvis and intractable urinary tract infection. The institutional review board at MSKCC approved the protocol, and an investigational new drug application was filed and approved by the US Food and Drug Administration. All patients provided written informed consent before entry onto the trial.

Intravesical Instillation
Gemcitabine was reconstituted and diluted in 100 mL of normal saline. The pH was adjusted to pH 5.5 to 7.0, with 8.4% sodium bicarbonate for every 1,000 mg of gemcitabine. The pH was adjusted to avoid any chemical cystitis resulting from the low pH of the reconstituted gemcitabine. The patient was instructed to avoid excessive fluid intake starting the day before treatment. The bladder was completely emptied by straight catheterization before the instillation. Patients were instructed to retain the drug for one hour before voiding, but no positional changes were required.

Study Design
Eligible patients received two courses of intravesical gemcitabine twice weekly at a dose of 2,000 mg/100 mL for 3 consecutive weeks, with each course separated by a week of rest. Patients were evaluated for response at the end of the eight weeks. Patients who did not respond were recommended to undergo a radical cystectomy. Patients demonstrating a complete response by cystoscopy, cytology, and bladder biopsy underwent close surveillance. The surveillance schedule included urine cytology and serial cystoscopies every 3 to 4 months to evaluate for recurrence, with biopsy of any suspicious mucosal lesions.

Pretreatment studies included an ECG and chest x-ray. Physical examination and assessment of toxicity were performed before each administration of chemotherapy. A CBC was obtained at the end of the 3-week cycle. A biochemistry panel examining electrolytes and liver enzymes was performed at the beginning of the first 3-week cycle of intravesical gemcitabine, and at the end of therapy. An evaluation under anesthesia with bladder biopsies was performed at the end of the intravesical therapy (approximately 1 week after the last dose of gemcitabine) to assess for response.

Intravesical treatment was discontinued if the patient developed neutropenic fever (absolute granulocyte count < 1,000 cells/mL³ at the time of a documented temperature of 38°C), documented bacteremia in the presence of neutropenia, grade 3 or 4 neutropenia or thrombocytopenia, bilirubin more than 1.5, or transaminases more than 3x normal, or if the patient developed grade 4 bladder toxicity. Gemcitabine instillation was postponed for 1 week if the patient developed grade 3 bladder toxicity, provided there was resolution of symptoms.

Statistical Analyses
Based on the observation of seven responses in the phase I trial, we chose to use a single-stage design for this phase II study. The prospectively designed sample size of 30 patients was chosen so that the response rate could be estimated with an SE of less than 18%. This SE was considered an acceptable width to proceed to a phase III trial if clinical activity was confirmed.

The goal of this trial was to assess response at 3 months, time to recurrence, and time to progression after gemcitabine therapy. Antitumor effects were defined as: CR in which the cystoscopy showed no suspicious lesions and/or biopsies and cytology were negative for malignancy; partial responses (PR) where cystoscopy and/or biopsies showed no malignancy but the cytology was positive; and nonresponse where residual disease was evident by cystoscopy and/or bladder biopsy. The following variables were recorded for every patient: survival time from start of treatment, status (alive/dead), response at 3 months (CR v PR, nonresponse), sex (male/female), age at treatment, recurrence status and date of recurrence, progression status and date of progression, and cystoscopy status and date. Recurrence-free survival time was defined as the time from the date of assessment of response to treatment, to the date of recurrence or last follow-up among patients who achieved a CR. Survival was estimated using Kaplan-Meier methodology. Time to progression was defined as the time from the date of assessment of response to treatment to the date of progression, cystectomy, or last follow-up. The incidence of progression was estimated using a competing risk analysis accounting for cystectomy as a competing risk.¹⁹

	RESULTS

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Patient Characteristics
Thirty-one patients were treated in this phase II study. One patient refused follow-up biopsy and was therefore excluded, resulting in 30 assessable patients. There were 22 men and eight women, for a male-female ratio of 7:3. The median age was 70 years with a range of 43 to 89 years. The highest stage of bladder cancer anytime in the natural history of the disease before starting intravesical gemcitabine was cis in 14 patients, T1 with or without cis in 14 patients, and high-grade Ta in two patients. The stage of the tumor immediately prior the intravesical instillation was cis in 23 patients, T1 in three patients, and incompletely resected high-grade Ta in three patients. Three patients were considered BCG intolerant: one patient because of local symptoms, one patient developed BCG sepsis, and one patient was receiving immunosuppression treatment after renal transplantation. Twenty-seven patients were considered BCG refractory (Table 1).

View larger version (8K): [in this window] [in a new window]   Fig 1. Recurrence-free survival among patients with a complete response (CR).

View larger version (7K): [in this window] [in a new window]   Fig 2. Incidence of progression and cystectomy.

Toxicity
Intravesical gemcitabine was generally well tolerated. Three patients developed a grade 2 dysuria defined by occasional pain or difficulty urinating, and six patients experienced grade 3 dysuria defined by continuous difficulty urinating characterized by pain and frequency. One patient developed a rash on the glans penis. A patient who was receiving immunosuppression for a renal transplantation developed a cellulitis of the leg, requiring intravenous antibiotics (Table 2). The toxicity encountered in this phase II study was similar to the toxicity we previously reported in our phase I trial.

	DISCUSSION

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Based on the results of the phase I study previously reported,¹⁸ we conducted a phase II study to evaluate the efficacy of intravesical gemcitabine in patients with BCG-refractory TCC. Two other groups have performed studies using a less intensive weekly schedule. Laufer et al²¹ reported a separate phase I study of weekly intravesical gemcitabine in 15 patients who received prior intravesical therapy. Serum gemcitabine levels were undetected at concentrations of 5 mg/mL, 10 mg/mL, 15 mg/mL, and 20 mg/mL, while low concentrations were present in all patients receiving 40 mg/mL. However, the metabolite dFdU (2'2'-difluorodeoxyuridine) was detectable in plasma of patients receiving gemcitabine at concentration of 15 mg/mL or higher, implying minimal absorption of gemcitabine at lower doses. The authors concluded that intravesical gemcitabine was well tolerated with minimal toxicity. Furthermore, no evidence of recurrence at 12 weeks was noted in nine of 13 assessable patients.²¹ De Berardinis²² reported no systemic detection of gemcitabine at a concentration of 40 mg/mL; however, the inactive metabolite was detected in plasma. They were able to demonstrate activity of deoxycytidine kinase in tissue samples, an enzyme that produces 2',2'-difluoro-deoxycytidine triphosphate, the active metabolite of gemcitabine.²² All reports published thus far confirmed the low systemic absorption of gemcitabine, and the good tolerability with minimal local and systemic toxicity,^23,24 on which we published and provided compelling reasons to investigate further the clinical potential of gemcitabine via the intravesical route.

Although a significant initial CR was achieved, the majority of patients experienced a relapse within 12 months. This is not unexpected given the mechanism of cytotoxicity for chemotherapy. The duration of therapy in this trial is brief by chemotherapy standards. Phase III trials of systemic chemotherapy are of 6 months’ duration,^17,25 the standard of care for unresectable or metastatic disease. Therefore, recurrent treatment with cytotoxic drugs is common with cytotoxic drugs in contrast to immunologic therapy, where recurrent immunotherapy is felt to induce a host response against the tumor. This may be one potential reason that BCG therapy is superior to chemotherapy approaches in general. One consideration to improve the durability of response is to consider maintenance therapy. Although the role of maintenance therapy for intravesical chemotherapeutic agents is controversial,^26-29 in a meta-analysis of 11 randomized trials, Huncharek suggested that chemotherapy for 2 years had the greatest effect on decreasing the recurrence rates.²⁷ This would not be unexpected given the log-cell-kill obtained with chemotherapy agents, provided that chemoresistance does not develop. No maintenance therapy was used in this trial, but the early CR with intravesical gemcitabine and the high recurrence rate warrants investigating the role of maintenance therapy in future trials.

A second consideration is that multiple-agent chemotherapy may be more successful than just using a single agent. Single-agent chemotherapy is extremely limited in curing systemic disease, and the best results have been achieved with multiple agents. The most common treatment for metastatic TCC is with the regimens consisting of gemcitabine plus cisplatin,¹⁷ or the four-drug combination MVAC.²⁵ Even the most curable cancer in uro-oncology, germ cell tumors, requires multiple chemotherapy agents. The synergistic activity between gemcitabine and other chemotherapeutic agents has been the basis for the introduction of new chemotherapeutic regimens in the management of metastatic disease.³⁰ However, using two different chemotherapeutic agents, taking advantage of their synergistic effect has not been attempted in intravesical approaches. In vitro studies have demonstrated a marked synergism between gemcitabine and mitomycin-C,³¹ the most commonly used intravesical chemotherapeutic agent. A phase II trial in metastatic breast cancer demonstrated in vivo synergism between gemcitabine and docetaxel.³² Intravesical docetaxel was well tolerated in a recently reported phase I trial,³³ making a combination of docetaxel and gemcitabine a viable option. Doxorubicin and gemcitabine combination was associated with in vivo synergism in metastatic breast cancer.³⁴ Collectively, these observations support the study of combining intravesical gemcitabine with other chemotherapeutic agents.

Other investigational approaches have been recently reported in BCG-refractory superficial disease. For example, BCG with interferon alfa has been explored with early success. Comparisons across these phase II studies are not possible due to the heterogeneity of the tumors, patient populations, and the definition of BCG-refractory. In evaluating salvage therapies for BCG failures, comparisons between therapies are seriously hampered by the lack of standard definitions for BCG failure and BCG-refractory TCC^35-37 and the methods of reporting the results.^18,20,38,39 Thus, the results of intravesical BCG and interferon alfa, a regimen commonly used in patients who were unsuccessfully treated with BCG, could not be compared with the results achieved in our trial because of the difference in the patient populations.⁴⁰ We defined BCG failure as persistence of disease after two consecutive courses of BCG, or any other situation associated with a high risk of progression: recurrent Tis within less than 6 months of achieving a CR after one or two courses of BCG, recurrent Tis while on maintenance therapy, or relapse with T1 disease. This definition identifies those tumors and patients with the worst outcome and is an attempt to describe a more homogeneous patient population and facilitate comparisons between future therapies. In contrast, in the study investigating BCG and interferon alfa, patients with recurrent Tis independent of time of recurrence, patients who failed only one cycle of BCG were included in the BCG failure group.⁴⁰

In summary, it is our strong belief that radical cystectomy still remains the best treatment for patients with BCG-refractory TCC. However, some patients are adamantly opposed to cystectomy because of the morbidity, and low perceived quality-of-life issues. Furthermore, a cystectomy might not be suitable for these patients with severe comorbidities. Thus, conventional treatments and investigational studies for these patients are clearly warranted. Despite the limited activity of gemcitabine, it remains a viable option for some patients, based on the clinical activity seen in the prospective trial. Lastly, clinical trials of novel intravesical agents in the BCG-refractory setting should be supported in order to improve the standard of care, since the treatment options for these patients is severely limited.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Dean Bajorin Lilly (C)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Guido Dalbagni, Dean Bajorin Financial support: Guido Dalbagni Administrative support: Guido Dalbagni Provision of study materials or patients: Guido Dalbagni, Paul Russo, Bernard Bochner, Joel Sheinfeld, Pramod Sogani, Machelle S. Donat, Harry W. Herr Collection and assembly of data: Guido Dalbagni Data analysis and interpretation: Guido Dalbagni, Leah Ben-Porat Manuscript writing: Guido Dalbagni, Dean Bajorin Final approval of manuscript: Guido Dalbagni

 

	NOTES

 
Supported by Eli Lilly and Co.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted December 8, 2005; accepted March 13, 2006.

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